Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits
Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits
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DOI：
10.1073/pnas.97.18.10197
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发表时间：
2000-08-29
影响因子：
11.1
通讯作者：
Bolli, R
中科院分区：
文献类型：
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作者：
Shinmura, K;Tang, XL;Bolli, R
我们研究了环氧合酶-2 (COX-2) 在缺血预适应 (PC) 后期的作用。总共使用了 176 只有意识的兔子。缺血性：PC（6 个周期的 4 分钟冠状动脉闭塞/4 分钟再灌注）导致心肌 COX-2 mRNA 水平快速增加（1 小时时 +231 +/- 64%；RNase 保护测定），24 小时后 COX-2 蛋白表达增加（+216 +/- 79%；蛋白质印迹）以及前列腺素 (PG)E-2 和心肌含量6-酮-PGF(1 α)（分别为+250 +/- 85% 和+259 +/- 107%；酶免疫测定）。缺血PC后24小时给予两种不相关的COX-2选择性抑制剂（NS-398和塞来昔布）消除了缺血PC诱导的PGE（2）和6-酮-PGF（1α）组织水平的增加。缺血性 PC 后 24 小时给予相同剂量的 NS-398 和塞来昔布，完全阻断了晚期 PC 对心肌顿抑和心肌梗死的心脏保护作用，表明 COX-2 活性是这种现象发生所必需的。 NS-398 和塞来昔布均不降低预处理兔子非缺血区域中的 PGE(2) 或 6-keto-PGF(1 α) 水平，表明组成性COX-1 活性不受影响。总之，这些结果表明，在清醒的兔子中，COX-2 的上调在缺血性 PC 晚期提供的心脏保护中起着重要作用。因此，本研究将COX-2确定为一种心脏保护蛋白。花生四烯酸代谢物的分析强烈表明PGE(2)和/或PGl(2)是COX-2依赖性保护的可能效应物。 COX-2 介导晚期 PC 的抗惊厥和抗梗塞作用的认识促使人们重新评估目前关于这种酶的观点，这种酶通常被认为是有害的。
We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic: PC (six cycles of 4-min coronary occlusions/4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (+231 +/- 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (+216 +/- 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E-2 and 6-keto-PGF(1 alpha) (+250 +/- 85% and +259 +/- 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE(2) and 6-keto-PGF(1 alpha). The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur, Neither NS-398 nor celecoxib lowered PGE(2) or 6-keto-PGF(1 alpha) levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE(2) and/or PGl(2) as the likely effecters of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.